Submissions for variant NM_000059.4(BRCA2):c.1123C>T (p.Pro375Ser)

gnomAD frequency: 0.00019  dbSNP: rs80358408

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083085	SCV000244417	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000648
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195325	SCV000071753	benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001719791	SCV000210556	likely benign	not provided	2020-12-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 18284688, 24916970, 15876480, 21990134, 17924331, 24323938, 23315985, 27153395, 26332594, 29580235)
Ambry Genetics	RCV000162998	SCV000213486	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000083085	SCV000220527	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-21	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000173635	SCV000224765	likely benign	not specified	2015-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173635	SCV000694510	benign	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1123C>T (p.Pro375Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 143210 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD v3 database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. This variant has been reported in the literature in individuals affected with breast- and ovarian cancer (Lee_2008, Salazar_2006, Peixoto_2014, Maistro_2016, Maxwell_2016). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.211A>G (p.Arg71Gly) in the NHGRI BIC database), providing supporting evidence for a benign role. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007 and Lindor_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as benign (3x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000162998	SCV000902815	benign	Hereditary cancer-predisposing syndrome	2016-08-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000083085	SCV001138989	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000195325	SCV002504842	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162998	SCV002533209	benign	Hereditary cancer-predisposing syndrome	2020-12-16	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000195325	SCV004014968	likely benign	Hereditary breast ovarian cancer syndrome	2023-04-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083085	SCV000115159	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083085	SCV000145815	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing